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    Clinical Trial Results:
    Efficacy and Safety of SAR156597 in the Treatment of Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Randomized, Double-blind, Placebo-controlled, 24-week, Proof of Concept Study

    Summary
    EudraCT number
    2016-001028-80
    Trial protocol
    DE   AT   BE   EE   IT  
    Global end of trial date
    01 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Apr 2020
    First version publication date
    10 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT14604
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02921971
    WHO universal trial number (UTN)
    U1111-1179-4690
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate, in comparison with placebo, the efficacy of SAR156597 administered subcutaneously for 24 weeks on skin fibrosis in subjects with diffuse cutaneous systemic sclerosis (dcSSc).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    97
    EEA total number of subjects
    52
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    88
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 13 countries. A total of 97 subjects were involved in the study from 21 December 2016 to 01 April 2019.

    Pre-assignment
    Screening details
    Subjects were randomised in 1:1 ratio (placebo and SAR156597). Randomisation was stratified based upon the subject’s medical history of systemic sclerosis (SSc) associated interstitial lung disease (SSc-ILD) (yes or no). Assignment was done by Interactive Voice Response System (IVRS).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (for SAR156597 200 milligram [mg]), single SC injection in abdomen.

    Arm title
    SAR156597
    Arm description
    SAR156597 200 mg, single SC injection QW up to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Romilkimab
    Investigational medicinal product code
    SAR156597
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR156597 200 mg, single SC injection in abdomen.

    Number of subjects in period 1
    Placebo SAR156597
    Started
    49
    48
    Completed
    43
    44
    Not completed
    6
    4
         Lack of efficacy
    3
    1
         Other than specified above
    2
    1
         Adverse Event
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24.

    Reporting group title
    SAR156597
    Reporting group description
    SAR156597 200 mg, single SC injection QW up to Week 24.

    Reporting group values
    Placebo SAR156597 Total
    Number of subjects
    49 48 97
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.2 ± 12.1 52.3 ± 10.8 -
    Gender categorical
    Units: Subjects
        Female
    38 39 77
        Male
    11 9 20
    Race
    Units: Subjects
        American Indian or Alska Native
    0 1 1
        Asian
    1 0 1
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    2 2 4
        White
    45 45 90
    Modified Rodnan Skin Score (mRSS)
    mRSS: an accepted clinical measure of the skin thickness (fibrosis). Investigator physicians or qualified medical personnel assessed the thickening of skin in 17 skin sites, including fingers, hands, forearms, arms, feet, legs and thighs, face, chest and abdomen. Each skin site was rated on a 0-3 scale; where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness and 3 = severe thickness. Total mRSS (sum of individual scores) ranged from 0 (normal skin) to 51 (severe thickening in all 17 areas), where higher score indicated more severity of skin thickening/worst outcome.
    Units: units on a scale
        arithmetic mean (standard deviation)
    20.6 ± 7.0 20.5 ± 6.1 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24.

    Reporting group title
    SAR156597
    Reporting group description
    SAR156597 200 mg, single SC injection QW up to Week 24.

    Primary: Change From Baseline in Modified Rodnan Skin Score to Week 24

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    End point title
    Change From Baseline in Modified Rodnan Skin Score to Week 24
    End point description
    mRSS, an accepted clinical measure of the skin thickness (fibrosis). Investigator physicians or qualified medical personnel assessed the thickening of skin in 17 skin sites including fingers, hands, forearms, arms, feet, legs and thighs, face, chest and abdomen. Each skin site was rated on a 0-3 scale; where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness and 3 = severe thickness. Total mRSS ranged from 0 (no thickening) to 51 (severe thickening in all 17 areas), where higher score indicated more severity of skin thickening/worst outcome. The analysis was performed on the intent to treat (ITT) population which included all randomised subjects and were analysed according to the treatment group allocated by randomisation. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR156597
    Number of subjects analysed
    48
    47
    Units: score on a scale
        least squares mean (standard error)
    -2.45 ± 0.85
    -4.76 ± 0.86
    Statistical analysis title
    SAR156597 Versus Placebo
    Statistical analysis description
    Analysis was performed using mixed model repeated measures (MMRM) model. The model included fixed categorical effects of treatment group, randomisation strata as per IVRS, timepoint, treatment-by-timepoint and strata-by-timepoint interactions, as well as the continuous fixed covariate of baseline and baseline-by-timepoint interactions.
    Comparison groups
    SAR156597 v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0291 [1]
    Method
    Mixed-effect model with repeated measure
    Parameter type
    Least square (LS) Mean difference
    Point estimate
    -2.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.71
         upper limit
    0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.21
    Notes
    [1] - Above p-value is one-sided p-value. Threshold for significance is at 0.05 level.

    Secondary: Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24

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    End point title
    Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 24
    End point description
    HAQ-DI assessed the degree of difficulty subjects experienced in 8 daily living activity domains during past week: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each activity category consisted of 2-3 items. For each items, level of difficulty was scored from 0-3 (0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do). Overall HAQ-DI score was computed as the sum of domain scores divided by the number of domains answered, providing a score from 0 (no difficulty) to 3 (maximum difficulty), where higher score indicated greater disability. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR156597
    Number of subjects analysed
    48
    47
    Units: score on a scale
        least squares mean (standard error)
    -0.12 ± 0.08
    -0.09 ± 0.08
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24

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    End point title
    Change From Baseline in Mean Observed Forced Vital Capacity (FVC) Level to Week 24
    End point description
    FVC was the total amount of air (in litres) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status of an underlying ILD. Change from Baseline was calculated by subtracting Baseline value from Week 24 value. Analysis was performed on the ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR156597
    Number of subjects analysed
    47
    47
    Units: litres
        least squares mean (standard error)
    -0.08 ± 0.04
    -0.01 ± 0.04
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24

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    End point title
    Change From Baseline in Mean Observed Diffusing Lung Capacity for Carbon Monoxide (DLco) to Week 24
    End point description
    DLco is a measurement of the ability of the lungs to transfer gases from the air to the blood. Subject breathe in (inhale) air containing a very small, harmless amount of a tracer gas, such as carbon monoxide. Subject hold the breath for 10 seconds, then rapidly blow it out (exhale). The exhaled gas was tested to determine amount of the tracer gas absorbed during the breath. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR156597
    Number of subjects analysed
    46
    47
    Units: millimoles per minute per kilopascal
        least squares mean (standard error)
    -0.27 ± 0.10
    -0.12 ± 0.10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) were collected from the signature of the informed consent form until the end of the study, regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported treatment-emergent AEs (TEAEs) & deaths were AEs that developed/worsened/became serious during TEAE period (time from 1st IMP administration up to 12 weeks [84 days] from last IMP dose [i.e. up to 36 weeks]). Safety population: subjects who received at least 1 dose/part of a dose of IMP and were analysed as per treatment actually received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR156597), single SC injection QW up to Week 24.

    Reporting group title
    SAR156597
    Reporting group description
    SAR156597 200 mg single SC injection QW up to Week 24.

    Serious adverse events
    Placebo SAR156597
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 49 (10.20%)
    4 / 48 (8.33%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Echocardiogram Abnormal
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal Pseudo-Obstruction
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Scleroderma Renal Crisis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo SAR156597
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 49 (55.10%)
    31 / 48 (64.58%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    0
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 48 (8.33%)
         occurrences all number
    1
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 49 (8.16%)
    7 / 48 (14.58%)
         occurrences all number
    5
    8
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    1
    4
    Skin Ulcer
         subjects affected / exposed
    15 / 49 (30.61%)
    8 / 48 (16.67%)
         occurrences all number
    23
    20
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 48 (8.33%)
         occurrences all number
    1
    4
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 48 (6.25%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    6 / 49 (12.24%)
    6 / 48 (12.50%)
         occurrences all number
    6
    6
    Oral Herpes
         subjects affected / exposed
    1 / 49 (2.04%)
    5 / 48 (10.42%)
         occurrences all number
    1
    7
    Pharyngitis
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 48 (10.42%)
         occurrences all number
    2
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2017
    Pulmonary function tests & echocardiogram were added at screening, & electrocardiogram (ECG) assessment was modified. Percent (%) predicted forced vital capacity (FVC) & observed & % predicted Carbon Monoxide diffusing lung capacity (DLco) (corrected for hemoglobin) & observed were added to Visit 1 (V1) to screen for newly added exclusion criteria (At screening, % predicted FVC is less than or equal to [<=] 75% & % predicted DLco after hemoglobin correction is <= 40%). A 2-Dimensional transthoracic echocardiogram was added to Visit 1 to screen for newly added exclusion criterion. Exclusion criteria was added: - History of heart failure (including acutely decompensated in the setting of preserved ejection fraction), Left Ventricular Ejection Fraction (LVEF) <=45%, coronary artery disease, angina, myocardial infarction, ischemic cardiomyopathy &/or hypertrophic cardiomyopathy. - Ischemic ECG changes (except those not supported by the findings of a left heart catheterisation performed in the last year within screening) &/or other clinically significant ECG findings at screening. (All abnormal ECG finding was reviewed & confirmed by a local cardiologist.) Electrocardiogram variables were updated: At Visit 1, all abnormal ECG interpretation was confirmed by a local cardiologist. All findings of ischemic ECG changes were to result in exclusion unless there was a left heart catheterisation performed in the last year within screening that is not supportive of the current ECG finding. Appendix for clinically significant ECG was added. Echocardiogram variable was updated: A standard 2-Dimensional transthoracic echocardiogram was to be obtained at Visit 1 (unless one had been previously obtained within 6 months of Visit 1) to help determine subject’s eligibility. At a minimum, the echocardiogram was to be able to assess for the LVEF & status & function of the four cardiac chambers, myocardium and valves.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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